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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

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Author(s):
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Stanley, Christopher P. [1] ; Maghzal, Ghassan J. [1, 2] ; Ayer, Anita [1, 2] ; Talib, Jihan [1, 2] ; Giltrap, Andrew M. [3] ; Shengule, Sudhir [1] ; Wolhuter, Kathryn [1] ; Wang, Yutang [4, 5, 6] ; Chadha, Preet [1] ; Suarna, Cacang [1] ; Prysyazhna, Oleksandra [7, 8] ; Scotcher, Jenna [7, 8] ; Dunn, Louise L. [1] ; Prado, Fernanda M. [9] ; Nguyen, Nghi [10] ; Odiba, Jephthah O. [10] ; Baell, Jonathan B. [10, 11] ; Stasch, Johannes-Peter [12] ; Yamamoto, Yorihiro [13] ; Di Mascio, Paolo [9] ; Eaton, Philip [7, 8] ; Payne, Richard J. [3] ; Stocker, Roland [1, 2]
Total Authors: 23
Affiliation:
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[1] Victor Chang Cardiac Res Inst, Darlinghurst, NSW - Australia
[2] Univ New South Wales, St Vincents Clin Sch, Sydney, NSW - Australia
[3] Univ Sydney, Sch Chem, Sydney, NSW - Australia
[4] Univ Sydney, Sch Med Sci Pathol, Ctr Vasc Res, Sydney, NSW - Australia
[5] Univ Sydney, Sydney Med Sch, Bosch Inst, Sydney, NSW - Australia
[6] Federat Univ Australia, Sch Hlth & Life Sci, Ballarat, Vic - Australia
[7] Kings Coll London, Cardiovasc Div, Dept Cardiol, London - England
[8] St Thomas Hosp, Rayne Inst, London - England
[9] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil
[10] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, Vic - Australia
[11] Nanjing Tech Univ, Sch Pharmaceut Sci, Nanjing, Jiangsu - Peoples R China
[12] Bayer AG, Cardiovasc Res, Wuppertal - Germany
[13] Tokyo Univ Technol, Sch Biosci & Biotechnol, Tokyo - Japan
Total Affiliations: 13
Document type: Journal article
Source: Nature; v. 566, n. 7745, p. 548+, FEB 28 2019.
Web of Science Citations: 3
Abstract

Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. (AU)

FAPESP's process: 12/12663-1 - Singlet molecular oxygen and peroxides in chemical biology
Grantee:Paolo Di Mascio
Support type: Research Projects - Thematic Grants
FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC